Paclitaxel (Taxol®) and docetaxel (Taxotère®) are two of the most important antitumor drugs approved for clinical use in chemotherapy against human tumors. Paclitaxel is a naturally occurring taxane, which was initially isolated from the bark of the Pacific yew tree, Taxus brevifolia. 
Docetaxel is a semi-synthetic congener of paclitaxel. Docetaxel is the first “taxoid,” i.e., Taxol-like compound, approved by the FDA for clinical use.
These two first-generation taxane anticancer agents have been clinically used to treat various tumors, including metastatic breast cancer, advanced ovarian cancer, head and neck cancers, non-small cell lung cancer, and Kaposi's sarcoma. Although both paclitaxel and docetaxel possess potent antitumor activity against some tumors, they do not show efficacy against others, such as colon, pancreatic, melanoma, and renal cancers.
In addition, the first generation taxanes are subject to undesirable side effects as well as multi-drug resistance (MDR) upon treatment. The MDR is usually attributed to cells that overexpress P-glycoprotein (Pgp). Pgp is an effective ATP-binding cassette (ABC) transporter which effluxes out hydrophobic anticancer agents, including paclitaxel and docetaxel.
Current cancer chemotherapy is based on the premise that rapidly proliferating tumor cells are more likely to be killed by cytotoxic drugs than healthy cells. However, in reality, the difference in activity of current drugs against tumor tissues compared to healthy tissues is relatively small.
For example, it is well known that representative cytotoxic chemotherapeutic agents like paclitaxel, cisplatin, doxorubicin, and other widely used anticancer drugs cannot distinguish cancer cells from normal dividing cells. Thus, a variety of undesirable side effects associated with these drugs occur in cancer chemotherapy.
Accordingly, a continuing challenge in cancer chemotherapy is to develop new cytotoxic agents with greater selectivity for tumor cells than healthy cells.
It has been shown that particular natural fatty acids are taken up greedily by tumors for use as biochemical precursors and energy sources. These fatty acids include omega-3 fatty acids such as docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and α-linolenic acid (LNA).
DHA is a constituent of cell membranes and is used as a precursor for metabolic and biochemical pathways. It is also a fatty acid found in human milk, and is classified as a nutritional additive by the United States Food and Drug Administration.
U.S. Pat. Nos. 5,795,909; 5,919,815 and 6,080,877 disclose DHA-conjugated to first generation taxane anticancer agents such as paclitaxel and docetaxel. DHA-paclitaxel conjugates have shown antitumor activity in animal studies. The ability of DHA-paclitaxel conjugates in reducing undesirable side effects is attributed to its selective targeting of the conjugates to tumor cells and use of lower doses compared to unconjugated paclitaxel.
For example, it has been reported (Bradley et al. Clinical Cancer Research (2000) 7, 3229-3238) that DHA-paclitaxel at the optimum dose of 120 mg/kg resulted in complete regression of lung tumor xenografts in a Madison 109 subcutaneous lung tumor model. The regression was sustained for sixty days in all mice. In mice, DHA-paclitaxel exhibits a 74-fold lower volume of distribution and a 94-fold lower clearance rate than paclitaxel. DHA-paclitaxel is stable in plasma, and high concentrations are maintained in mouse plasma for a long period of time. In contrast, paclitaxel at the optimum dose of 20 mg/kg caused neither complete nor partial regression of the tumors in any mice. The conjugate drug appears to be inactive as a cytotoxic agent until metabolized by tumor cells to release palitaxel.
Therefore, DHA-paclitaxel is less toxic than paclitaxel alone. As a result, higher molar doses of the conjugate can be administered. On the basis of the efficacy demonstrated in animal models, DHA-paclitaxel entered human clinical trials, and is currently in Phase III.
Accordingly to the proposed drug-delivery mechanism, DHA-paclitaxel is taken up by tumor cells, internalized, and slowly hydrolyzed by esterases in the cancer cell to release the active cytotoxic agent (e.g., paclitaxel). However, if the cancer cells are overexpressing an active transporter (i.e., “efflux pump”), the paclitaxel molecules, even when released slowly from DHA, will be caught by the efflux pump and eliminated from the cancer cells. Thus, the efficacy of DHA-paclitaxel can be rendered not sufficiently active against drug-resistant cancers.
The structure-activity relationship (SAR) study performed in the inventor's laboratories has shown that the phenyl moieties of paclitaxel at the C-2, C-3′, and C-3′N positions are not essential for its potent cytotoxicity and tubulin-binding ability (Ojima et al. J. Med. Chem. (1996) 39, 3889-3896). The inventor and his coworkers found that the incorporation of a simpler alkyl or alkenyl substituent at C-3′ considerably increased activity against drug-sensitive as well as drug-resistant cancer cell lines. More importantly, appropriate modifications at the C-10 and C-3′ positions have led to the development of “second-generation” taxoid anticancer agents. The most significant result with this series of taxoids was their substantially increased potency against drug-sensitive human cancer cell lines as well as remarkable activity against drug-resistant cell lines, expressing MDR phenotypes (e.g., IC50=2.1-9.1 nM; paclitaxel IC50=300-800 nM against human breast cancer cell line MCF7-MDR). The second-generation taxoids also include a series of taxoids bearing pentacyclic diterpene skeleton derived from 14-hydroxybaccatin III.
Thus, in sharp contrast with paclitaxel and docetaxel, the second-generation taxoids including ortataxel (code names in publications include Bay59-8862, IDN5109 and SB-T-101131), SB-T-1213 and SB-T-121303, exhibit excellent activity against drug-resistant cancer cells expressing MDR phenotypes. For example, ortataxel exhibited impressive activity against human colon carcinoma SW-620 xenografts in mice (Vredenburg et al. J. Nat'l Cancer Inst. (2001) 93, 1234-1245).
However, these highly potent second-generation taxoids are not tumor specific. Thus, various undesirable side effects may occur during clinical use.
Accordingly, there is a need for improved anticancer drugs for effectively treating all types of cancer, including multi-drug resistant tumors, while diminishing side effects.